This proposed UM1 phase 2 supplement brings together teams from NCI-designated comprehensive cancer centers at Mayo Clinic, University of Maryland, Columbia University, and the University of Iowa to collectively perform early phase clinical trials. Members of this proposed ETCTN team have accrued 3939 patients to phase 2 clinical trials from 2010 through 2014, demonstrated expertise in translational science, and established specialized facilities to develop biomarkers for clinical trials, including the Mayo Clinic Pathology Research Core and CLIA-certified University of Maryland Translational Genomic Laboratory. We now propose to conduct phase 2 clinical trials of NCI-sponsored anti-cancer agents to evaluate the clinical activity and biological impact of these agents on their molecular targets, elucidate other relevant biologic effects, and determine the correlation between clinical outcomes and relevant biomarkers and/or imaging endpoints. The goal of these studies is to not only determine, as efficiently as is compatible with patient safety, the effectiveness of new anticancer agents selected by the NCI or promising combination therapies and high- priority agents that are pivotal for drug development, but also facilitate the correlativ science needed to understand and properly develop these agents. The intent is to seamlessly move studies from phase 1 into phase 2 and to bring forward therapeutic approaches that can be incorporated into phase 3 clinical trials sponsored by other mechanisms. Studies will be designed using clinical endpoints that are appropriate for the therapeutic mechanism of the specific agent under study such as response, time to progression, progression- free rate at a point in time or survival. Importantly, alternative or secondary endpoints for the studies to be performed under this supplement may include changes in biomarker endpoints or imaging endpoints, including changes in blood flow and/or alterations in tumor metabolic activity. Accordingly, the specific aims of this proposal are to: i) determine the clinical activity, efficac and safety of novel anticancer agents and combinations selected by NCI for evaluation of therapeutic activity across a range of malignancies, whether chosen by histological subtype or molecular profile; ii) efficiently and seamlessly take promising therapies from phase 1 into phase 2 trials; iii) evaluate translational endpoints such as levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent or pathway modulated by the agent under study; iv) identify and test potential biomarkers (with particular emphasis where possible on genomics and imaging) that may serve as predictors of efficacy or toxicity; and v) translate preclinical science and new discoveries from R01, SPORE or other peer reviewed mechanisms into clinical trials that leverage the expertise of the scientific community using a team science approach.